Sudden cardiac death (SCD) is a leading cause of deaths from cardiovascular diseases. SCD is resultant from regular loss of heart rhythm due to myocardial electrophysiological instability such as sustained ventricular tachycardia (VT) and ventricular fibrillation (VF) which are the most serious cases.
Antiarrhythmic drugs can be divided into four classes. Class I are sodium channel blockers, which can be further divided into subtypes a, b and c, wherein Class Ia, as represented by Quinidine, moderately block the sodium channel; Class Ib, as represented by Lidocaine, block the sodium channel in a milder way and Class Ic, as represented by Flecainide, significantly block the sodium channel. Class II are β-adrenoreceptor blockers, as represented by Propranolol. Class III, as represented by Amiodarone, selectively prolong the repolarization process including action potential duration (APD) and effective refractory period (ERP). Class IV, as represented by Verapamil, are calcium antagonists.
Isoquinoline alkaloids are widely found in natural plants. Certain isoquinoline alkaloids, like bisbenzylisoquinoline alkaloids (eg, berbamine, dauricine, tetrandrine, cocculine, neferine) and monobenzylisoquinoline alkaloids (such as higenamine) and protoberberine (Huangliansu), have cardiovascular activities, like anti-arrhythmia activity. Berberine exhibits a class-III antiarrhythmic activity and has been reported as useful in treating ventricular arrhythmia in clinic.
Since 1985, Ms. Meihua Xie (Research Fellow) from Shanghai Institute of Pharmaceutical Industry has designed and synthesized nearly 1,000 compounds that were derived from higenamine and berberine as the leading compounds via structural reconfiguration. These compounds were tested on antiarrhythmic pharmacodynamics, Ames toxicity, acute toxicity and pharmacokinetics, whereby 1-(3-methanesulfonamidobenzyl)-6-methoxy,7-benzyloxy-1,2,3,4-tetrahydroisoquinoline (referred to as “SIPI-409” herein below) of formula (II) was picked out as a candidate for a new antiarrhythmic drug for preclinical studies:

1-(3-methanesulfonamidobenzyl)-6-methoxy,7-benzyloxy-1,2,3,4-tetrahydroisoquinoline (SIPI-409) and its hydrochloride salt, as well as the preparation and uses thereof were described in Chinese Patent No. ZL200710181295.7.
However, further studies found that SIPI-409 and its hydrochloride salt were less soluble in water, as demonstrated by the solubility as low as 0.07 mg/mL (0.15 nmol/mL) and 0.51 mg/mL (1.05 nmol/mL), respectively. At the same time, preliminary pharmacokinetic studies have shown that t1/2 of SIPI-409 hydrochloride injection was close to that of Sotalol, while oral administration of SIPI-409 hydrochloride gave a bioavailability (24%) far lower than Sotalol (70%) in SD rats. This can be explained by the excessively low solubility of the salt.
Therefore, there is a need for a salt derivative of the compound with improved water solubility, bioavailability and druggability.